Emory University chemistry scientists have demonstrated the ability to selectively functionalize the unreactive carbon-hydrogen (C-H) bonds of an alkane without using a directing group, while also maintaining virtually full control of site selectivity and the three-dimensional shape of the molecules produced.

First, a little background. Alkanes are the simplest of organic molecules, consisting only of hydrogen and carbon atoms. In chemistry, the original name for alkane was paraffin, which is Latin for “lacking reactivity.”

Huw Davies, an Emory professor of organic chemistry whose lab led the research explained, “Alkanes are cheap, plentiful raw materials that are considered non-functional, or unreactive, except in uncontrollable situations, such as burning them. Our work, however, shows that it is indeed possible to efficiently functionalize an alkane in a controlled manner. We’ve actually changed the way that the description of alkanes in organic chemistry textbooks needs to be written.”

This is quite early in the discovery, but holds enormous implications across a wide field. The Emory team is focused on medical uses, but a lot of industry is going to take notice, especially fossil, bio and synthetic fuel engineers.

The journal Nature has publishing the work by the chemists at Emory University.

Davies starts us off with an overview, “The catalyst control we have found goes beyond what has been achieved before. We’ve designed a catalyst that provides a huge shortcut for how chemists can turn a simple, abundant molecule into a much more complex, value-added molecule. We hope this gives people a fundamentally new view of what can be achieved through C-H functionalization.”

The streamlined process described in the paper holds tremendous potential for the synthesis of fine chemicals. The Emory press release points out applications such as those needed for the development of pharmaceuticals.

“Organic synthesis is all about simplicity,” Davies said. “It may lead to a sophisticated outcome, but it has to be simple to carry out in order to have practical applications.”

Davies is also director of the National Science Foundation’s Center for Selective C-H Functionalization (CCHF), which is based at Emory and encompasses 15 major research universities from across the country, as well as industrial partners.

The CCHF is leading a paradigm shift in organic synthesis, which has traditionally focused on modifying reactive, or functional, groups in a molecule. C-H functionalization breaks this rule for how to make compounds: It bypasses the reactive groups and does synthesis at what would normally be considered inert carbon-hydrogen bonds, abundant in organic compounds.

The fact that multiple C-H bonds are commonly present in a single organic molecule, however, presents a significant challenge to this new type of chemistry. Chemists experimenting with C-H functionalization normally use a directing group – a chemical entity that combines to a catalyst and then directs the catalyst to a particular C-H bond.

“The directing group has to be introduced and then removed,” Davies explained. “It works fine but the process is cumbersome.”

The Davies lab bypassed the need for a directing group by developing a series of dirhodium catalysts encased within a three-dimensional scaffold. The scaffold acts like a lock and key to allow only one particular C-H bond in a compound to approach the catalyst and undergo the reaction.

“We had already demonstrated that we could do site selectivity of C-H bonds in molecules where C-H bonds are fairly activated,” Davies said. “Here, we’ve gone for the ultimate challenge – the extremely unreactive C-H bonds of alkanes.”

In addition to controlling site selectivity, the scaffold of the dirhodium catalysts developed by the Davies lab controls the chirality of the product produced in the reaction.

Chirality, also known as “handedness,” refers to a property of three-dimensional symmetry. Just as the human hand is chiral, because the right hand is a mirror image of the left, molecules can be “right-handed” or “left-handed.”

The handedness of a molecule is important in organic chemistry, since this 3D shape affects how it interacts with other handed molecules. For example, when developing a new drug it is vital to control the chirality of the drug molecules because biological molecules recognize the difference.

The Emory press release uses the infamous drug thalidomide as the most notorious example of the handedness problem. During the late 1950s, thalidomide was sold as an over-the-counter drug for pregnant women suffering from morning sickness.

Davies explained, “It’s difficult to make molecules with one mirror image, so many older drugs were a mixture of both. It was thought that one mirror image would be biologically active, and the other wouldn’t matter.” In the case of thalidomide, however, while one mirror image cured morning sickness, the other turned out to cause birth defects.

Today, pharmaceutical makers must either limit a drug’s molecules to a single chiral shape, or go through the extra time and expense of testing the safety of a mixture of left-handed and right-handed molecules. The new C-H functionalization catalyst may pave the way to a whole new realm of materials for drug discovery research.

“The starting material we used, pentane, is as cheap as gasoline, but we are able to efficiently generate a sophisticated product in a single step and control which mirror image is formed,” Davies said.

The process is also more sustainable than traditional organic synthesis, which typically involves the use of many reagents, and can produce toxic, inorganic byproducts.

“In contrast, our catalyst speeds up a reaction but is not used up in a reaction,” Davies says. “Only a tiny amount of the catalyst is needed to produce a lot of product. And the only byproduct is nitrogen, which is innocuous.”

While the Nature paper “opens the door” to a new method for C-H functionalization, more work is needed, Davies said. “We need to understand how to use it predictably and demonstrate its use in complex target applications.”

This is a huge effort, with 15 U.S. research universities forming the core of the CCHF, as well as major research universities in Japan, South Korea and the United Kingdom.

This technology will take a while to develop, prove up, scale and commercialize. For now it looks to be a major breakout kind of discovery. Congratulations are in order to the team along with Davies including first author of the Nature paper Emory chemistry graduate student Kuangbiao Liao, Solymar Negretti and John Bacsa (from Emory’s Department of Chemistry) and Djamaladdin Musaev (from Emory chemistry and the Cherry L. Emerson Center for Scientific Computation).


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